The adrenocorticolytic activity of 1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane; (o,p′-DDD, Mitotane®, Lysodren®) was first described in 1949 in dogs. Adrenal toxicity of o,p′-DDD is known to result from a cytochrome P450 (CYP)-catalysed formation of an reactive acyl chloride on the ethane side chain; this metabolite subsequently becomes irreversibly bound in the adrenal cortex, in several species including humans. The irreversible binding to vital cellular macromolecules is assumed to be of importance for the adrenal toxicity of o,p′-DDD. Metabolic activation and irreversible binding of o,p′-DDD is, however, not specific for the adrenal cortex but can occur also in other organs, such as the lung and liver. By virtue of its adrenal toxicity, o,p′-DDD is currently used as an adrenocorticolytic drug for treatment of adrenocortical carcinoma and Cushing's syndrome (1). The effective dose for treatment of adrenocortical cancer is high and gives a plasma concentration above 14 μm/ml (44 μM), whereas plasma concentrations below 10 μg/ml (31 μM) are therapeutically insufficient. Only one-third of the patients (194 out of 551) who were not cured by surgery, responded to o,p′-DDD treatment (1). In addition to hypocortisolism, o,p′-DDD gives rise to dose-dependent side effects in the gastrointestinal tract (nausea, vomiting and diarrhea) and CNS (dizziness and headaches). Treatment-related unspecific effects such as weakness and fatigue are also observed. In a substantial proportion of patients, these side effects are intolerable at therapeutic doses and the drug has to be withdrawn.
Aryl methyl sulphones of DDE and PCBs were first identified in blubber of Baltic grey seal. The sulphones form in the mercapturic acid pathway, involving sequential metabolic transformation during entero-hepatic circulation. Several of the methyl sulphones are characterized by a highly cell- and tissue-selective distribution pattern in mice. 1-(4-Chloro-3-methylsulphonylphenyl)-1-(4-chlorophenyl)-2,2-dichloroethene (MeSO2-[14C]DDE) was originally found to give rise to a cell-specific irreversible binding to cellular macromolecules in mouse adrenal zona fasciculata cells in vivo. MeSO2-DDE was subsequently demonstrated to be a highly potent adrenal toxicant that induces mitochondrial degeneration and cellular necrosis following a CYP11B1-catalyzed metabolic activation in the murine adrenal cortex (2). In addition, reduced plasma corticosterone levels were observed following exposure to MeSO2-DDE (3). Both the irreversible protein binding and the toxicity of MeSO2-DDE in the adrenal zona fasciculata were effectively blocked by the CYP 11B1-selective enzyme inhibitor metyrapone in mice.